Endometriosis occurs when cells from the mucus membrane lining the uterus (endometrium) form implants that attach, grow, and function outside the uterus, generally in the pelvic region. Endometrial cells contain receptors that bind to estrogen and progesterone, which promote uterine growth and thickening. During endometriosis these cells become implanted in organs and structures outside the uterus, where these hormonal activities continue to occur, causing bleeding and scarring. Endometrial implants vary widely in size, shape, and color (accessed at http://www.endogynwiki.com/endometriosis/what-is-the-endometriosis-disease/). Endometriosis probably affects about 10 to 15% of menstruating women aged 25 to 44.1 In North America 5.5 million women have this gynecological disorder.2 Endometriosis is recognized as the third leading cause of gynecologic hospitalization in developed countries and a major reason for hysterectomy.3 
Endometriosis may be found in 24% to 50% of women who experience infertility, and in more than 20% who have chronic pelvic pain.4 In women with severe menstrual cramps, the incidence of endometriosis has been reported to be between 25% and 35%.5 Other common symptoms include pain in the lower abdomen, pain during intercourse (dyspareunia), abdominal bloating, diarrhea, constipation, rectal bleeding, blood in the urine, and menstrual irregularities, such as heavy menstrual bleeding and spotting before menstrual periods. The symptoms usually disappear during pregnancy and after menopause (however, they may be present in menopausal women receiving estrogen replacement therapy).
Symptomatic endometriosis often requires appropriate therapy. Treatment selection is driven by the severity and type of symptoms, stage and location of the disease, a woman's age and reproductive (pregnancy) plans.
When endometriosis-induced pain is present, non-steroidal anti-inflammatory drugs (NSAIDs) may be used for temporary relief of this symptom. Inevitable dose increases (for episodes of acute incapacitating pain) or extended dosing periods (for management of chronic pain) may lead to undesirable outcomes, including gastro-intestinal and cardiovascular side effects. Some menstrual symptoms, including heavy bleeding and/or painful menstrual period, may be controlled by hormonal contraceptives. For a number of women, the treatments may not be acceptable due to known contraindications, hormone-related adverse events and/or undesirable changes in the menstrual bleeding pattern, including unpredictable intra-cyclic bleeding, irregular menstrual periods and/or development of amenorrhea.
In a majority of women, endometriosis responds to steroid hormonal therapy. The goal is to suppress production of endogenous estrogens supporting the proliferation of endometrium and the growth of endometrial implants. Increased androgen and/or progestin action also induces atrophy of the endometrium. There are medications such as gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide acetate, goserelin acetate, and nafarelin) and androgens (e.g., danazol) which are approved for the treatment of endometriosis. However, the prolonged hypoestrogenic state which develops during treatment with these agents may also result in undesirable outcomes, including decrease in bone density, development of osteoporosis, and menopausal symptoms such as amenorrhea, hot flashes, mood swings, etc. For this reason, GnRH agonists and androgens are not recommended for long-term use. Treatment with GnRH agonists is limited by approved labeling to 6 months; danazol therapy may last up to 9 months. Following GnRH therapy, immediate add-back medications (combined or progestin-only contraceptives, combination estrogen-progestin hormone replacement regimens, bisphosphonates, etc.) may be required. Importantly, the described medications generally do not cure endometriosis; at best they temporarily reduce the size of endometrial implants while suppressing some of the symptoms.
Surgical removal of endometriosis and restoration of normal pelvic conditions is achievable via various procedures described elsewhere (see, for example, reference 1). Recurrent disease and accompanying symptoms and subsequent surgical procedures cannot be ruled out. In the most severe cases, hysterectomy with removal of the uterus and both ovaries may be the only option. Hysterectomy is a major surgical procedure used to permanently resolve the endometriosis-related symptoms. However, removal of the uterus is a radical treatment option with known undesirable characteristics, including loss of fertility, surgical morbidity and high cost.
While a number of promising candidates have been identified among selective estrogen receptor modulators (SERMs), aromatase inhibitors, anti-inflammatory drugs, and immune modulators, there is still an unmet need for an effective and safe pharmacological treatment of endometriosis.6 
Selective progesterone receptor modulators (SPRMs) are a class of drugs acting on progesterone receptors and display progesterone antagonist or mixed agonist/antagonist activity.7 The oldest member of this class, mifepristone, is considered as a progesterone antagonist (anti-progestin, anti-progestational agent).11 Numerous compounds in this pharmacological class have been synthesized; some of them have been tested in clinical trials in women diagnosed with endometriosis. Efficacy and safety studies were conducted for two orally administered SPRMs: asoprisnil (Clinicaltrials.gov Identifier NCT00160420) and CDB-4124 (Proellex®; Clinicaltrials.gov Identifiers NCT00556075 and NCT00958412).
While the mechanism of action of SPRMs and anti-progestins is not completely understood, there is growing biochemical, histologic and clinical evidence that SPRMs and anti-progestins may have a critical role in controlling endometriosis growth. Studies have suggested that the compounds display direct antiproliferative effects in the endometrium in a dose-dependent fashion.8 These effects are accompanied by an increase in progesterone, estrogen and androgen receptors and are thought to be related to progesterone antagonism and mixed progestin agonist and antagonist activity. Estrogen-dependent endometrial proliferation, mitotic and secretory activities are suppressed, and endometrial thickness and wet weight are reduced.9 Other pharmacodynamic properties of SPRMs and anti-progestins (such as direct effects on endometrial vasculature and inhibition of ovulation) may also contribute to the development of amenorrhea9,10, considered beneficial for women with endometriosis.
A number of clinical studies have evaluated the efficacy and safety of oral mifepristone in the treatment of gynecological disorders.13,14,15,16,17,18 The data suggests that 10 mg/day or higher oral doses of mifepristone are effective in the reduction of uterine and fibroid volumes and related symptoms. However, at this dose, the incidence of side effects such as endometrial hyperplasia, hot flashes and elevated liver enzymes seems to be greater than desired. Two clinical programs of other SPRMs were discontinued for safety reasons. Phase III studies of oral asoprisnil were terminated due to changes in the endometrial lining of the uterus that resulted in additional invasive procedures in some patients. Phase III studies of another compound of the same class—oral CDB-4124 (Proellex®)—were suspended because of significant increases in liver enzymes. While a 5 mg/day oral mifepristone dose may be a safer alternative, its ability to reduce uterine volume and eliminate some of the fibroid-related symptoms is limited. A further oral dose reduction (2.5 mg/day) may be harder to justify due to an appreciably smaller reduction of uterine volume and a lower incidence of amenorrhea, with no noted benefits of therapy extending beyond the initial three months.18 
Several clinical studies have investigated mifepristone in the treatment of endometriosis. In one of the trials, six normally cycling women with endometriosis were given orally 100 mg mifepristone daily for three months. Amenorrhea was reported by all study participants; all women also reported improvement in pelvic pain (notably, most patients received alternative treatment for endometriosis prior to enrollment in that study with no reduction in pain). However, no significant change in the extent of endometriosis was evident from follow-up laparoscopy.19,20 
In another clinical trial, nine women with endometriosis received mifepristone orally, 50 mg daily for 6 months. Pelvic pain and uterine cramping improved in all patients and endometriosis regressed by 55% as evidenced by laparoscopic assessments of endometrial implants using the American Fertility Society (AFS) score. All patients exhibited amenorrhea without hypoestrogenism. Elevation of liver transaminases was observed in one subject.21 
When the same group of researchers conducted the third clinical study in seven women with endometriosis using oral dose of mifepristone of 5 mg daily administered for 6 months, pelvic pain improved in six of seven patients and cyclic bleeding ceased in all patients; however, four women complained of irregular bleeding and mean endometriosis scores decreased by only 20%. Based on these data, the authors recommended the 50 mg mifepristone dose.22 However, as was shown before, such a high dose may lead to the increased risk of endometrial hyperplasia and clinically significant elevations in liver enzymes (see, for example, reference 13).
Taken together, the clinical evidence indicates that the efficacy of oral mifepristone (or another SPRM, anti-progestin, or anti-progestational agent) in the treatment of gynecological disorders must be weighed against the potentially disturbing side effects associated with this medication.
Effectiveness and safety of intravaginal drug delivery is supported by a substantial body of evidence. It is established for estrogens used to treat vaginal atrophy and related symptoms25, as well as osteoporosis and other menopausal symptoms.26 Other examples of compounds efficacious after vaginal administration include (but are not limited to) misoprostol for cervical ripening27, a danazol ring for the treatment of infiltrating endometriosis28, and a progesterone gel.29,30 The contraceptive efficacy of levonorgestrel (LNG)-containing intrauterine system, Mirena® with 20 mcg/day LNG delivery is at least comparable to that reported for the LNG-only pill delivering a 50% greater daily dose. As noted in the Mirena NDA Medical review, serum concentrations of levonorgestrel for Mirena are approximately one-tenth the serum concentration produced by an oral contraceptive containing 0.1 mg LNG and about half that produced by the Norplant® system. The local endometrial concentrations, however, are over 100 times higher in Mirena users than in users of oral contraceptives containing 0.25 mg LNG.31 Important findings were also reported from clinical studies evaluating the systemic and local LNG concentrations and possible mechanisms of LNG delivery and action in women with endometriosis.32 The clinical data from another study indicated the possibility of direct LNG effects mediated through estrogen and progestogen receptors on the endometrial implants themselves.33 